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DIFFERENTIATION OF EXHAUSTED CD8 T CELLS AFTER TERMINATION OF CHRONIC ANTIGEN STIMULATION STOPS SHORT OF ACHIEVING FUNCTIONAL T CELL MEMORY
Tonnerre, Pierre et al. | Date Issued: 2021
Author
Tonnerre, Pierre
Wolski, David
Subudhi, Sonu
Al-Jabban, Jihad
Hoogeveen, Ruben C.
Damasio, Marcos
Drescher, Hannah K.
Bartsch, Lea M.
Tully, Damien C.
Sen, Debattama R.
Bean, David J.
Brown, Joelle
Torres-Cornejo, Almudena
Robidoux, Maxwell
Kvistad, Daniel
Alatrakchi, Nadia
Cui, Ang
Lieb, David
Cheney, James A.
Gustafson, Jenna
Lewis-Ximenez, Lia L.
Massenet-Regad, Lucile
Eisenhaure, Thomas
Aneja, Jasneet
Haining, W. Nicholas
Chung, Raymond T.
Hacohen, Nir
Allen, Todd M.
Kim, Arthur Y.
Lauer, Georg M.
Affilliation
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA / Inserm U976, Institut de Recherche Saint-Louis, Paris, France.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA / Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA / Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA..
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.
Inserm U976, Institut de Recherche Saint-Louis, Paris, France.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA / Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA / Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA / Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA..
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract
T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.
Keywords in Portuguese
Exaustão de células T
Recuperação imunológica
Infecção por HCV
Terapia antiviral
 
Keywords
T cell exhaustion
Immunological recovery
HCV infection
Antiviral therapy
 
Publisher
bioRxiv
Citation
TONNERRE, Pierre et al. Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. bioRxiv preprint, p. 1-49, Apr. 2021.
DOI
10.1101/2021.04.03.437705